Allosteric modulation of G protein‐coupled receptors by amiloride and its derivatives. Perspectives for drug discovery?
| Autor: | Arnault Massink, Tasia Amelia, Adriaan P. IJzerman, Alex Karamychev |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Allosteric regulation
Review Article Receptors G-Protein-Coupled Amiloride 03 medical and health sciences 0302 clinical medicine G protein-coupled receptors Allosteric Regulation G protein‐coupled receptors Drug Discovery medicine N-hexamethylene)amiloride 5‐(N N‐hexamethylene)amiloride Animals Humans Binding site Receptor Review Articles 030304 developmental biology G protein-coupled receptor Pharmacology 0303 health sciences allosteric modulation Drug discovery Chemistry Small molecule 5-(N 030220 oncology & carcinogenesis Biophysics Molecular Medicine Sodium ion binding hormones hormone substitutes and hormone antagonists medicine.drug |
| Zdroj: | Medicinal Research Reviews Medicinal Research Reviews, 40(2), 683-708 |
| ISSN: | 1098-1128 0198-6325 |
| Popis: | The function of G protein-coupled receptors (GPCRs) can be modulated by compounds that bind to other sites than the endogenous orthosteric binding site, so-called allosteric sites. Structure elucidation of a number of GPCRs has revealed the presence of a sodium ion bound in a conserved allosteric site. The small molecule amiloride and analogs thereof have been proposed to bind in this same sodium ion site. Hence, this review seeks to summarize and reflect on the current knowledge of allosteric effects by amiloride and its analogs on GPCRs. Amiloride is known to modulate adenosine, adrenergic, dopamine, chemokine, muscarinic, serotonin, gonadotropin-releasing hormone, GABA(B), and taste receptors. Amiloride analogs with lipophilic substituents tend to be more potent modulators than amiloride itself. Adenosine, alpha-adrenergic and dopamine receptors are most strongly modulated by amiloride analogs. In addition, for a few GPCRs, more than one binding site for amiloride has been postulated. Interestingly, the nature of the allosteric effect of amiloride and derivatives varies considerably between GPCRs, with both negative and positive allosteric modulation occurring. Since the sodium ion binding site is strongly conserved among class A GPCRs it is to be expected that amiloride also binds to class A GPCRs not evaluated yet. Investigating this typical amiloride-GPCR interaction further may yield general insight in the allosteric mechanisms of GPCR ligand binding and function, and possibly provide new opportunities for drug discovery. |
| Databáze: | OpenAIRE |
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